One of the most important ways of dealing with intravenous drug abuse and the spread of AIDS is to provide effective pharmacological treatments. Buprenorphine has been identified as a potentially useful treatment for intravenous abuse of both opiates and cocaine. The current proposal aims to produce analogs of buprenorphine with similar pharmacological profiles to buprenorphine but differentiated by their levels of mu intrinsic activity. Of particular interest would be an orally active mu partial agonist with lower intrinsic activity than buprenorphine. Such an analog would be less liable to abuse than buprenorphine and be useful in facilitating transfer of patients to the pure antagonist treatment naltrexone but also could be developed as an analgesic alternative to codeine. The medicinal chemistry program will involve the resynthesis of selected analogs to determine their opioid receptor profile and synthesis of new close analogs to explore structure-activity relationships (SAR) involving the tertiary alkyl function. Molecular graphics will be used to relate SAR to conformation of the analogs at C19 particularly to test the hypothesis that there are two lipophilic sites on the opioid receptor relating to mu and to K intrinsic activity respectively. A further test of this hypothesis will be provided by the synthesis and testing of analogs with conformations constrained by being part of appropriate alicyclic systems. A major part of the program will be the investigation of the effect of halogenation in the aromatic nucleus of some of these analogs. This modification has been shown to reduce intrinsic activity at mu and K receptors and to enhance affinity, sometimes selectively. As an extension of the investigation of the effect of halogenation it is proposed to prepare halogenated oxymorphones. The N-methyl series could provide mu partial agonists whereas the substituted naltrexones are starting materials for analogs of the specific antagonists cryprodime (mu), norbinaltorphimine (nor BNI; K) and naltrindole (delta) which could be improvements on the unhalogenated parents.